Method for the synthesis of clofarabine

Abstract

The present invention relates to a method for the high yield production of the anticancer nucleoside clofarabine, the method comprising the preparation of 2-chloroadenosine by enzymatic transglycosylation between 2-chloroadenine and nucleosides, benzoylation, isomerization, sulfonate ester formation, fluorination, and deprotection.

The invention claimed is: 
     
       1. Method for the production of clofarabine, comprising:
 (a) preparing 2-chloroadenosine by enzymatic transglycosylation between 2-chloroadenine and a compound of formula 1, 
 
       
         
           
           
               
               
           
         
         
           wherein, R 1  is purine or pyrimidine base of formula 2 or formula 3, respectively, 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 2  and R 3  are independently selected from the group consisting of —H, —NH 2 , —OH, and —CH 3 ; and 
           R 4  is selected from the group consisting of —H and —CH 3 ; 
         
         (b) partially protecting the hydroxyl groups of 2-chloroadenosine to obtain a mixture of a compound of formula 4 and a compound of formula 5, 
       
       
         
           
           
               
               
           
         
          wherein R 5  is independently a hydroxyl protecting group; 
         (c) isomerizing the compound of formula 4 to the compound of formula 5; 
         (d) preparing a compound of formula 6 from the compound of formula 5, 
       
       
         
           
           
               
               
           
         
          wherein OR 6  is a leaving group; 
         (e) fluorinating the compound of formula 6 to a compound of formula 7; and 
       
       
         
           
           
               
               
           
         
         (f) deprotecting the compound of formula 7 to obtain clofarabine. 
       
     
     
       2. The method of  claim 1 , wherein the transglycosylation in step (a) is performed by using purine nucleoside phosphorylase or a combination of purine nucleoside phosphorylase and uridine phosphorylase. 
     
     
       3. The method of  claim 1 , wherein the fluorination in step (e) is performed by using a fluorinating agent. 
     
     
       4. The method of  claim 3 , wherein the fluorinating agent is selected from the group consisting of hydrofluoric acid and a mixture of hydrofluoric acid and an organic Lewis base. 
     
     
       5. The method of  claim 4 , wherein the organic Lewis base is an amine. 
     
     
       6. The method of  claim 1 , wherein R 1  is a pyrimidine base representing uridine. 
     
     
       7. The method of  claim 1 , wherein R 5  is a hydroxyl protecting group representing benzoyl. 
     
     
       8. The method of  claim 1 , wherein OR 6  is a leaving group representing trifluoromethanesulfonate.